When a drug is systemically administered to an individual orally or by intravenous injection, etc., side effects may be recognized at normal tissues other than the focal lesions to be targeted, which may force the modification and/or suspension of the therapeutic regimen. Also for some drugs, it may be difficult to maintain the effective drug concentration, or some may be metabolized before being delivered to the target site.
In order to resolve these problems, active research is currently underway on technologies that will have introduced advanced pharmaceutical methods and concepts in which the control of the pharmacokinetics or selective delivery of a drug in the body leads to the desired drug concentration/time pattern at the action site of interest in order to optimize the therapeutic effect. These technologies and concepts are referred to as the drug delivery system (DDS), and in recent years growing importance has been recognized in that they permit the safer and more effective delivery of anti-cancer drugs, DNA, peptides etc. to pathological lesions such as tumor sites and inflammatory sites.
As specific means of DDS, a method that employs liposomes, emulsions, or nanoparticles as the drug carrier, a method in which drugs are incorporated in polymer carriers such as polymeric micelles, a method in which drugs are covalently bound to synthetic polymers or naturally occurring polysaccharides, and the like have been developed. In attempts to put these systems into practical use, there are various problems to be solved, and, among them, evasion from the biological mechanism of recognizing foreign objects, the containment of a drug at a high concentration in a DDS drug carrier, and the control of the release rate of a drug are posing serious challenges.
With regard to evasion from the biological mechanism of recognizing foreign objects, it is becoming possible to avoid the capture at the reticuloendothelial system (RES) of the liver, the spleen etc. by enhancing drug stability in the blood by coating the surface of a drug carrier such as liposomes with a hydrophilic polymer such as polyethylene glycol thereby preventing the adhesion of serum proteins, opsonin proteins etc. As a result, the high retention of liposomes and polymeric micelles in the blood circulation after intravenous administration can be obtained, and they have come to be passively accumulated in such tissues as the tumor tissues and inflammatory sites in which vascular permeability has been enhanced, thereby leading to efficient treatment.
On the other hand, with reference to the content of a drug in DDS drug carriers, a high drug content can reduce the amount of the carrier required to deliver the desired drug, which is advantageous in terms of both therapeutic effects and drug design [J. Med. Chem. 45: 4336-4343 (2002)]. Nevertheless, with regard to liposomes and polymeric micelles, the content of drugs is limited due to a poor physical stability thereof, and with regard to the polymer conjugate type, increases in drug content can affect the properties of water-soluble polymers, thereby reducing water solubility. As a result, their interaction with plasma components can no longer be controlled, retention of the conjugate in the blood circulation becomes impossible, and in most cases the drug content therein is as low as several percents [CRIPS 5(2): 2-8 (2004)]. Thus, it is impossible at present to attain a high drug content and an excellent retention in the blood at the same time.
For example, Japanese Unexamined Patent Publication (Kokai) No. 2003-34653 discloses a DDS compound which has been optimized and of which therapeutic range has been substantially expanded by a specific means for optimizing DDS, and describes that DDS compounds that make use of characteristics of each anti-cancer drug can be generated by selecting the sequence of a peptide linker for conjugating the drug and a carrier and the structure of the carrier. However, the content of anti-cancer drugs is merely about 1-10% relative to the total weight of the DDS compound.
With regard to the release of a drug, an ideal system in terms of reduced side effects and enhanced therapeutic effects is such that the drug is stably encapsulated in or bound to the carrier in the blood and, after reaching the lesional tissue, the drug is quickly released.
For example, Japanese patent No. 3270592, Japanese Unexamined Patent Publication (Kokai) No. 7-69900, and WO97/12895 disclosed pharmaceutical preparations of block copolymer-anthracycline anti-cancer drug. The drug has been encapsulated by physicochemical bonding or an amide bond utilizing the amino acid group of the drug and the carboxyl group of the block copolymer. Thus, the drug has been bound to the carrier and stabilized, but it is hardly conceivable to be quickly released after reaching the pathological tissue.
In order to highly realize the control of drug release, various environment-responsive carriers are being investigated, i.e. pharmaceutical carriers of which properties change in response to environmental changes resulting from diseases, or to differences in the environment of the normal tissue and the focal lesions.
For example, there has been reported HPMA copolymer-doxorubicin (PK1) in which doxorubicin has been bound to a HPMA polymer with a molecular weight of about 30,000 dalton via a GFLG spacer. In PK1, the drug is released by cathepsin B that is more expressed at tumor sites than at the normal tissues, and the drug content is 8.5%, i.e. it has not attained high drug content.
On the other hand, investigations are being made to attain the release of drugs in response to environmental changes due to pH changes at pathological lesions such as tumor sites and inflammatory sites by utilizing the fact that local pH at these affected regions is lower than at the normal tissues [Adv. Drug Delivery Rev. 56: 1023-1050 (2004), Biochim. Biophys. Acta. 1329(2): 291-301 (1997)].
An intracellular low-pH environment-responsive polymer conjugate [J. Controlled Release 87: 33-47 (2003)] and polymeric micelles [Bioconjugate Chem. 16: 122-130 (2005)] that release doxorubicin hydrochloride precisely in response to the low-pH environment in the endosome after the drug was incorporated into individual cancerous cells at local tumors via the endocytosis route have been reported. For this polymeric micelles, specifically, the pH dependence of drug release and a relatively high drug content have been attained.
The present inventors have found, however, that the increase in the amount of the drug in said polymeric micelles leads to reduced drug retention in the blood, and thus after intensive and extensive research, the present inventors have attained a high drug content and succeeded in enhancing retention in the blood.